Figure 9.

Proposed mechanism of LPS signaling in microglia leading to endothelial, and microglial
cell death. LPS binds toll-like receptor 4 (TLR4) on the surface of microglia leading to signaling
in several pathways., NF-κB, the MAPKs and JAK-STAT. MAPKs then activate JNK (JNK
kinase) and the p38 MAPK (p38). NF-κB, JAK-STAT and to a lesser extent, JNK lead to
upregulation of immune factors iNOS and NADPH oxidase (NOX). These factors lead to
the production of nitric oxide (NO) and superoxide (O2-), respectively. These molecules
are themselves known to be directly cytoxic, but may also combine to form peroxynitrite
(ONOO-) which can also kill cells. Also indicated in the figure are the NF-κB, p38
MAPK, JAK-STAT and JNK inhibitors studied. (PDTC = pyrrolidinecarbodithoic acid).